DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application, filed on 28 July, 2023, claims domestic benefit to US provisional applications no. 63/509,136 filed on 20 June, 2023 and no. 63/393,350 filed on 29 July, 2022.
Status of Application
The response filed on 10 March, 2026 has been entered in full. The response is amendment to a Non-Final Rejection to the claim set filed on 10 January, 2024. In the amendment, claims 1,2 5-10, 13-15, 18, 19, 22, 26, 28, 54, 56, and 57 are amended, and claims 3, 4, 11, 12, 16, 17, 20, 21, 23-25, 27, 29-53, 55, 58-103 are canceled. Therefore, claims 1, 2, 5-10, 13-15, 18, 19, 22, 26, 28, 54, 56, and 57 are pending and are the subject of this office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 22 February, 2024 has been considered by the examiner.
The information disclosure statement (IDS) submitted on 29 February, 2024 has been considered by the examiner.
The information disclosure statement (IDS) submitted on 10 March, 2026 has been considered by the examiner.
Status of Objections and Rejections
In the office action of 02/05/2026
Claims 3, 4, 11, 29, 30, 59, 88, and 90 were rejected under 35 U.S.C. 103 over Valamehr and Morgan. The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
Claims 1, 2, 5-10, 13-15, 18, 19, 22, 26, 28, 54, 56, and 57 were rejected under 35 U.S.C. 103 over Valamehr and Morgan. The amendment of these claims necessitates a modified form of the 103 rejection over Valamehr and Morgan.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 2, 5-10, 13, 14, 18, 19, 22, 26, 28, 54, 56, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Valamehr et al. (WO 2021/071962) in view of Morgan et al. (2020) Use of Cell and Genome Modification Technologies to Generate Improved “Off-the-Shelf” CAR T and CAR NK Cells Front. Immunol 11:1965 (hereafter Morgan).
In regards to instant claims 1, 2, and 15 Valamehr teaches a derivative effector cell (defined in the specification as including, immune cells (page 50, paragraph 000159) comprising a CAR, wherein the derivative effector cell is derived from a differentiated genetically engineered iPSC, and the iPSC comprises a polynucleotide encoding the CAR (genetic modification) and optionally one or more modifications. These modifications include the (iii) knockout in one or both CD58 and CD54 and (viii) deletion or reduced expression in at least one of a list of genes which includes RFX5 and NLRC5 (of instant claim 15) (claim 41). Further Valamehr discusses HLA class II deficiency can be achieved by functional deletion or reduction of HLA-II associated genes including, not being limited to, RFXANK, CIITA, RFX5, and RFXAP (pg. 62, paragraph 000183) and CD58 knockout has a higher efficiency in reducing allogenic NK cells activation than CD54 knockout (pg.63, lines 6-7).
In regards to instant claims 5 and 10, Valamehr teaches a derivative effector cell comprising a CAR, wherein the derivative effector cell is derived from a differentiated genetically engineered iPSC, and the iPSC comprises a polynucleotide encoding the CAR (Claim 41).
In regards to instant claim 6, Valamehr teaches a derivative effector cell comprising a CAR (claim 41) wherein the CAR is knocked in using targeted editing comprising deletion, insertion, or in/del, and wherein the targeted editing is carried out by CRISPR, ZFN (zinc finger), TALEN, homing nuclease, homology recombination, or any other functional variation of these methods (Claim 44).
In regards to instant claims 7-9, Valamehr teaches that genetic modification can be achieved by exogenous polynucleotide integration at specific sites and that these polynucleotides encode RNA including siRNA, shRNA, and miRNA (all of which are RNA interference sequences) (pg. 90, paragraph 000242). Further Valamehr teaches that genes of interest for knock out include RFX5 and CD58 (pg.78, paragraph 000213).
In regards to instant claim 13, Valamehr teaches the derivative effector cell derived from a differentiated genetically engineered iPSC cell comprising the CAR of Claim 1 (Claim 41), and claim 1 of Valamehr further teaches the CAR when comprised in an iPSC promotes differentiation of the iPSC to a derivative effector cell and the iPSC derived effector cell has at least one of a list of characteristics which includes (iv) increased resistance to allorejection.
In regards to instant claim 14, Valamehr teaches resistance against alloreactive immune cell rejection wherein the alloreactive immune cell rejection is alloreactive T Cell mediated and/or alloreactive NK cell mediated, by reduced or eliminated HLA-I or HLA-II expression (pg.62, paragraph 000183). This is evidenced by Morgan which teaches important conditions of “off the shelf” immune cells include avoidance of rejection due to recognition by host T cells via HLA class I molecules or host NK cells by HLA class II receptors (pg.4, col 1, lines 24-27) and a lack alloreactivity to limit unwanted toxicities due to recognition and destruction of healthy host tissue. Further, Morgan teaches “veritable “off-the-shelf” cell therapeutics will likely require genetic engineering strategies that address multiple layer of immune recognition patterns and cytotoxic mechanism” (pg.4, col 1 lines 37-39). Thus, the teachings of Valamehr teach the development of an immune cell which is resistant to T-cell and/or NK-cell mediated alloreactive immune cell rejection.
In regards to instant claims 18 and 19, Valamehr teaches a derivative effector cell comprising a CAR and optionally one or more edits which can result in a list of modifications. These modifications include the (ii) β2m null or low expression in comparison to its counterpart primary cell (claim 41). Due to it being optional Valamehr teaches both a derivative effector cell with both modified or unmodified β2m expression.
In regards to instant claim 22, Valamehr teaches derivative effector cell comprising a CAR, and optionally one or more edits which can result in a list of modifications. These modifications include the (ii) β2m null or low expression in comparison to its counterpart primary cell, (iii) knockout in one or both CD58 and CD54, and (viii) deletion or reduced expression in at least one of a list of genes which includes NLRC5 and RFX5 (claim 41). Valamehr also teaches that HLA class I deficiency can be achieved by deletion or reducing the expression level of HLA class-I associated genes including, not being limited to, β2M gene, TAP1 gene, TAP2 gene, and Tapasin and HLA class II deficiency can be achieved by functional deletion or reduction of HLA-II associated genes including, not being limited to, RFXANK, CIITA, RFX5, and RFXAP (page 62, paragraph 000183). Valamehr further teaches that an iPSC and its
derivative cells with both HLA-I and HLA-II deficiency enable allogeneic cell therapies by eliminating the need for MHC (major histocompatibility complex) matching (page 62, paragraph 000183). Therefore, knockdown of both HLA-I and HLA-II together or independently is encompassed in claim 41 of Valamehr.
In regards to instant claim 26, Valamehr teaches a cell or population thereof wherein the cell comprises at least one CAR (claim 19) and further wherein teaches the cell or population thereof of claim 19 can comprise the (iii) knockout in one or both CD58 and CD54 and (viii) deletion or reduced expression in at least one of a list of genes which includes NLRC5 and RFX5 (claim 21). Valamehr also teaches an exogenous polynucleotide integration into the locus of a TCRa gene to knockout the expression of the gene (Claim 34).
In regards to instant claim 28, Valamehr teaches a cell or population thereof wherein the cell is an immune cell from a primary source (pg.33, lines 23-25).
In regards to instant claim 54, Valamehr teaches a method of manufacturing a derivative effector cell comprising a CAR, wherein the derivative effector cell is derived from a differentiated genetically engineered iPSC, and the iPSC comprises a polynucleotide encoding the CAR and optionally one or more edits resulting genomic modifications.
In regards to instant claims 56 and 57, Valamehr teaches a therapeutic use of the composition of claim 35 by introducing the subject suitable for adoptive cell therapy, further claim 35 refers to a composition comprising the cell or population thereof of claim 21, which refers to a derivative effector comprises at least one CAR and one or more modification which can include (ii) β2m null or low expression in comparison to its counterpart primary cell, (iii) knockout in one or both CD58 and CD54, (viii) deletion or reduced expression in at least one of a list of genes which includes NLRC5, TRAC, CIITA, TAP2, and RFXANK, and (ix) introduced or increased expression in at least one of a list of genes which includes HLA-E, in comparison to it counterpart primary cell.
Valamehr fails to state explicitly using a CAR-T cell of instant claim 1 and the cells being derived from a healthy donor of claim 28.
Morgan, however, in regards to claim 1 teaches that T cells have significant anti-cancer immune activity (pg.2 col 1, lines 32-36) and CAR-T cells have been efficacy in liquid tumors and are showing promising results in solid tumors (pg.2, col 2, lines 1-6), further Morgan teaches T cells engineered to express CARs have amplified cytotoxic activity (pg.2, col 2, lines 50-55).
In regards to claim 28 Morgan teaches that cells derived from diseased patients (autologous) may be adversely affected in heavily pre-treated patients so that the quality and number of cells for ex vivo modification and donor cells (allogenic) cells lower the risk of genetically modifying and re-infusing leukemic cells and can be prepared and stored for future use (pg.4 col 1, lines 3-15).
Thus, Valamehr discloses all of the modification and embodiments claimed in the instant application as options to construct an engineered immune cell with impaired of reduced expression of RFX5 and CD58 and optionally NLRC5 relative to a cell without genomic modification, and Morgan teaches the success of CAR-T cells in the treatment of liquid and solid tumors and further teaches healthy donor obtained primary cells as a beneficial option. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to try combinations of the teachings of Valamehr informed by the teachings of Morgan with a reasonable expectation of success to develop a CAR-T cell with reduced expression of RFX5 and CD58 and optionally NLRC5 which is an effective cytotoxic treatment against tumors.
Response to Arguments
Applicant's arguments filed 10 March 2026 have been fully considered but they are not persuasive.
In response to applicant’s argument stating “Valamehr teaches inactivation of genes including CD58 in iPSCs and the effect of gene inactivation on the ability of the iPSCs to differentiate into potent effector cells. Nothing is said about T cells or the possible effect of CD58 inactivation in T cells” (remarks, pg.5, “claim rejections under 35 U.S.C. 103”, paragraph 2) with respect to claim 1 has been considered but is not persuasive because of the modified grounds of rejection necessitated by the amendment of the claim. The modification in view of Morgan which supports Valamehrs to give motivation for the selection CAR-T cells. Thus the 35 U.S.C. 103 rejection of claim 1 is maintained.
In response to applicant’s argument that “Valamehr does not teach or suggest a combination of CD58 and RFX5” (remarks, pg.5, “claim rejections under 35 U.S.C. 103”, paragraph 2), the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, while Valamehr does not explicitly teach the combination of CD58 and RFX5 in examples, it does suggest the combination in the claims where it suggest multiple mutations which in include a first mutation to knockdown of CD58 or CD54 with a second mutation to knockdown a second gene from a list including RFX5, thus suggesting the combination of CD58 and RFX5 as a potential option to combine. MPEP 2121.02 (II) also states “ the fact that an author of a publication did not attempt to make the compound disclosed, without more, will not overcome a rejection based on that publication.”
Valamehr further provides motivation to combine the gene knockouts. Valamehr points out the functions of both CD58 and RFX5 (pg. 62, paragraph 000183/ pg.63, lines 6-7) and how they would be beneficial in CAR cell development to avoid immune rejection as further clarified in the modified rejection of claim 1 above. Thus the 35 U.S.C. 103 rejection of claim 1 is maintained.
In response to applicant's argument that “Valamehr proposes an astronomical number of possible genes and gene combinations that could be inactivated in immune cells. Morgan does not narrow this selection but merely proposes inactivation of “MHC molecules”” (remarks, pg.6, “claim rejections under 35 U.S.C. 103”, paragraph 4).
Valamehr while reciting mutations of any gene in the chromosome 6p21 region distinctly points out a list of 12 genes know in the art to considered, further the 6p21 region is highly characterized and has identified genes associated with defense and Immunity (Herbo et al, of record, remarks 3/10/2026) thus a person of ordinary skill in the art would have the skills and knowledge to make reasonable choices in the selection of genes. Further, in the MPEP 2143(I)(E) it is stated “ that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense.” Thus, while Valamehr’s recitation of the 6p21 gene create a significantly large list, the suggestion of distinct genes (for which it is noted encompasses the RFX5 claimed in the instant application) and the highly characterized nature of the 6p21 gene renders the list of genes to a person of ordinary skill in the art reasonably finite and of identified predictable solutions. Thus, the 35 U.S.C. 103 rejection of claim 1 is maintained.
In response to applicant's argument that “without experimental evidence, one of ordinary skill in the art would not have an expectation that any untested combination would work in this setting” (remarks, pg.7, “claim rejections under 35 U.S.C. 103”, paragraph 5).
The MPEP states “obviousness does not require absolute predictability” (MPEP 2143.02(II)) and further states ”Conclusive proof of efficacy is not required to show a reasonable expectation of success” (MPEP 2143.02(I)). Valahmer suggest the combinations of the genes known in the art and further demonstrates that the combination of these gene can lead to cells with the desired modifications, thus providing a reasonable expectation that the combination of genes of known function in the art would allow for the development of and engineered CAR-T cell with impaired functional expression of target genes. Thus, the 35 U.S.C. 103 rejection of claim 1 is maintained.
Claims 2, 5-10, 13-15, 18, 19, 26, 28, 54,56, and 57 35 U.S.C. 103 rejections are maintained in light of their dependence on claim 1 and no further arguments presented.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. CHENG HSIN YUAN ET AL: "Generation of hypoimmunogenic allogeneic CART cells by inactivation of transcriptional regulators of HLA Class I and II genes", JOURNAL FOR IMMUNOTHERAPY OF CANCER, vol. 10, no. Suppl. 2, 210, 7 November 2022. (of IDS 22 Feb 2024) appears to be related to the instant application. This document discloses the reduced express or knockdown of NRLC5, RFX5 and 2m using CRISPR/Cas9 to develop autologous CAR T cells which is disclosed in the instant application. The document was published after the effectively filed date. It is not prior art against the claims.
Applicant's amendment necessitated the new grounds of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday – Thursday from 8am to 6pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-1977. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.A.A/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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